Musculoskeletal problems are pervasive throughout the population in all age groups and in both sexes. Half of Americans will need services for fractures at some point in their lifetime according to a widely published article presented at the 2003 annual meeting of the American Academy of Orthopedic Surgeons (AAOS). More than $10 billion per year is spent in the U.S. on hospital care associated with fracture treatment according to this report.
Bone health is an increasingly important issue as over 25 million people suffer from osteoporosis and 7 million more experience bone fractures annually in the United States. Osteoporosis and poor bone health contribute significantly to impaired bone structure leading to facile bone fracture and compromised bone repair. According to the Society of Cardiovascular and Interventional Radiology, osteoporosis causes about 700,000 fractures of the vertebrae each year.
Many factors can contribute to poor bone health. Several factors are excessive alcohol consumption, smoking, poor diet, physical inactivity, and genetic predisposition. Moreover, aging and osteoporosis contribute to decreased bone mass and mineral density as well as decreased bone fracture healing rates. Potential contributory factors to decreased bone healing rates in osteoporotic individuals include a reduction in the maturation of osteoblast progenitor cells, reduction in proliferative osteoprogenitor cell activity, decrease in bone forming capacity of mature osteoblasts, reduced osteoblastic response to chemical signaling, and a negative imbalance between bone formation and bone resorption.
Healthy bone may be deleteriously affected by weakened bone or by compensatory mechanisms that affect the load on the healthy bone. A patient with an injury on one side of the body, for example a fractured hip or an impaired femur due to avascular necrosis or osteoarthritis, may favor the injured side and add load to the contralateral hip or femur. Within the vertebral column, a diseased vertebra may add stress to adjacent vertebrae above or below it, eventually causing damage to these vertebrae. What is needed is a method to strengthen these otherwise healthy bones that are subject to additional stress and potential damage in order to prevent or mitigate such damage.
Vertebral compression fractures (VCFs) are the most common osteoporotic fractures, occurring in about 20% of post-menopausal women (Eastell et al., J Bone Miner Res 1991; 6:207-215). It is estimated that 700,000 VCFs occur annually, and only 250,000 of these are diagnosed and treated. Because these fractures are left untreated, osteoporosis may remain untreated and progress rapidly. Post-menopausal women have a 5-fold increased risk of sustaining another vertebral fracture within the coming year and 2-fold increased risk of other fragility fractures, including hip fractures (Klotzbuecher et al, J Bone Miner Res, 2000; 15:721-739).
VCFs occur when there is a break in one or both of the vertebral body end plates, usually due to trauma, causing failure of the anterior column and weakening the vertebrae from supporting the body during activities of daily living. Vertebral compression fractures caused by osteoporosis can cause debilitating back pain, spinal deformity, and height loss. Both symptomatic and asymptomatic vertebral fractures are associated with increased morbidity and mortality. With the number of aged people at risk for osteoporosis is expected to increase dramatically in the coming decades, accurate identification of VCFs and treatment intervention is necessary to reduce the enormous potential impact of this disease on patients and health care systems.
Traditionally, VCFs caused by osteoporosis have been treated with bed rest, narcotic analgesics, braces, and physical therapy. Bed rest, however, leads to accelerated bone loss and physical deconditioning, further aggravating the patient as well as contributing to the problem of osteoporosis. Moreover, the use of narcotics can worsen the mood and mentation problem that may already be prevalent in the elderly. Additionally, brace wear is not well-tolerated by the elderly. Although the current treatments of osteoporosis such as hormone replacement, bisphosphonates, calcitonin, and parathyroid hormone (PTH) analogs deal with long-term issues, except for calcitonin, they provide no immediate benefit in terms of pain control once a fracture occurs (Kapuscinski et al., Master Med. Pol. 1996; 28:83-86).
Recently, minimally invasive treatments for vertebral body compression fractures, vertebroplasty and kyphoplasty, have been developed to address the issues of pain and fracture stabilization. Vertebroplasty is the filling of a fractured vertebral body with the goals of stabilizing the bone, preventing further collapse, and eliminating acute fracture pain. Vertebroplasty, however, does not attempt to restore vertebral height and/or sagittal alignment. In addition, because there is no void in the bone, vertebral filling is performed under less control with less viscous cement and, as a consequence, filler leaks are common.
Kyphoplasty is a minimally invasive surgical procedure with the goal of safety, improving vertebral height and stabilizing VCF. Guided by x-ray images, an inflatable bone tamp is inflated in the fractured vertebral body. This compacts the inner cancellous bone as it pushes the fractured cortices back toward their normal position. Fixation can then be done by filling the void with a biomaterial under volume control with a more viscous cement. Although kyphoplasty is considered a safe and effective treatment of vertebral compression fractures, biomechanical studies demonstrate that cement augmentation places additional stress on adjacent levels. In fact, this increased stiffness can decrease the ultimate load to failure of adjacent vertebrae by 8 to 30% and provoke subsequent fractures (Berlemann et al., J Bone Joint Surgery BR, 2002; 84:748-52). Compression fracture of one or more vertebral bodies subsequent to vertebroplasty or kyphoplasty is referred to herein as a “secondary vertebral compression fracture.”
In a recent clinical study, a higher rate of secondary vertebral compression fracture was observed after kyphoplasty compared with historical data for untreated fractures. Most of these occurred at an adjacent level within 2 months of the index procedure. After this two-month period, there were only occasional secondary vertebral compression fractures which occurred at remote levels. This study confirmed biomechanical studies showing that cement augmentation places additional stress on adjacent level. (Fribourg et al., Incidence of subsequent vertebral fracture after kyphoplasty, Spine, 2004; 20; 2270-76).
Given the increased incidence of the use of minimally invasive surgical techniques for the treatment of vertebral compression fractures, and the predisposition of adjacent vertebrae to undergo secondary compression fracture, an unmet clinical need exists to prophylactically treat and prevent secondary VCFs.
Fractures of the distal radius are an important public-health problem and a major source of morbidity in the elderly. An estimated 1.4 million hand and forearm wrist fractures occur annually, and of these, nearly half (44%) are fractures of the ulna and radius. In the United States, 17% of all emergency room visits are due to wrist injuries [Hanel et al., Orthop. Clin. North Am. Jan. 33(1): 35-57 2002]. Distal radius fractures account for one sixth of all fractures seen in the emergency department (McMurtry et al., Fractures of the Distal Radius, 1992). Nearly one in four women will sustain a fracture of the distal radius by age 90, resulting in approximately 200,000 fractures annually in the United States with an estimated direct cost of nearly $150 million (Phillips et al., Bone 1988, 9:271-9, 1986). Further, because they occur most often in post-menopausal, osteoporotic women, these women have diminished bone density, which makes their fractures particularly troublesome to treat and susceptible to re-fracture.
Currently, there is no consensus on the preferred treatment of distal radius fractures. Typically, stable fractures receive closed reduction and immobilization in a plaster cast. Unstable distal radius fractures, however, may be treated with percutaneous pins incorporated in a plaster cast, metal external skeletal-fixation with or without pins and/or bone graft, limited open reduction with or without bone grafting, or extensive open reduction and internal fixation with or without pins and/or bone graft.
Recent reports have demonstrated the ability of volar fixed-angle plates to provide more stable internal fixation for surgical procedures that require open reduction and internal fixation (ORIF), and decrease subsequent morbidity in the treatment of unstable distal radius fractures compared to other internal fixation techniques (Orbay et al., J. Hand. Surg. 29A, 96-102, 2004).
The surgical assessment to determine a treatment plan based on the various fracture morphologies can be complex. Treatment-based fracture classifications are often used to determine the optimal treatment and attempt to predict an outcome based on the fracture pattern. A clinically useful classification system should assist the surgeon to evaluate and describe the fracture pattern, help select a therapeutic modality to treat the fracture, and be prognostic of the clinical outcome. The universally accepted AO System is a detailed fracture classification organized in order of increasing severity for both the bony extra- and intra-articular involvements. Type A fractures are extra-articular fractures that do not invade the articulating surface(s); type B describes limited articular fractures; and type C involve complex articular fractures. Each type is further divided into three subgroups based on the morphological complexity, treatment difficulty, and clinical prognosis.
In some cases, distal radius fractures require bone graft to ensure adequate bone healing. One of the most widely used options for bone graft is autologous bone. There have been problems, however, associated with autograft, including disadvantages associated with autologous bone grafting. Most of these problems result from the harvest of the bone graft, including increased operative time, hospital stay, cost, increased blood loss, post-operative pain, risk of infection and/or fracture. Other complications associated with autograft include a potential nidus for infection associated with avascular bone, limited tissue supply, and variability in cellular activity of the bone graft (Younger et al., J. Orthop. Trauma, 3, 192-195, 1989). The morbidity associated with autograft demonstrates the need for a better alternative for a chemotactic, mitogenic, and angiogenic bone graft substitute as an alternative for fracture augmentation.
In view of the significant health issues presented by poor bone health and bone diseases, such as osteoporosis, it would be desirable to provide compositions operable to facilitate bone fracture healing processes and promote healthy bone remodeling activities. It would additionally be desirable to provide methods of treating fractured or otherwise impaired bone with compositions operable to promote fracture healing and healthy bone remodeling processes. In view of the difficulties associated with autologous bone grafts, it would be desirable to provide alternative osteogenic regeneration systems. It would additionally be desirable to provide alternative osteogenic regeneration systems in bone fracture treatments, including fractures of bones such as the distal radius and associated anatomical structures of the wrist.